Recent Developments in the Treatment of Hypertension Recent Developments in the Treatment of...

Recent Developments in the Recent Developments in the Treatment of HypertensionTreatment of Hypertension

The Value of FactsThe Value of Facts

19991999

ObjectivesObjectives

• To review recent clinical trial evidence of efficacy To review recent clinical trial evidence of efficacy for antihypertensive agentsfor antihypertensive agents

• To present new data on the treatment of To present new data on the treatment of hypertensive patients with type 2 diabeteshypertensive patients with type 2 diabetes

• To discuss the emerging evidence for use of To discuss the emerging evidence for use of ACE inhibitors in diabetesACE inhibitors in diabetes

• To review recent safety data on antihypertensive To review recent safety data on antihypertensive agentsagents

Documentation of DrugDocumentation of DrugSafety and EfficacySafety and Efficacy

• Patients, clinicians and the health-care Patients, clinicians and the health-care establishment expect adequate documentationestablishment expect adequate documentation

• A week-long treatment for an acute condition A week-long treatment for an acute condition requires randomized trials that follow patients for requires randomized trials that follow patients for >> 1 week 1 week

• Lifelong treatments are ideally evaluated in lifelong Lifelong treatments are ideally evaluated in lifelong trials, but evaluations in large populations over 4 to trials, but evaluations in large populations over 4 to 5 years are typically accepted5 years are typically accepted..

Antihypertensive Drugs: DocumentationAntihypertensive Drugs: DocumentationBy the Time of Regulatory ApprovalBy the Time of Regulatory Approval

• BP lowering potential (N = 200-500 patients)BP lowering potential (N = 200-500 patients)

• Common side effects (symptoms)Common side effects (symptoms)

• Any common early drug complications (events)Any common early drug complications (events)

• Major changes in blood chemistryMajor changes in blood chemistry

• Major animal toxicityMajor animal toxicity

KnownKnown

Antihypertensive Drugs: DocumentationAntihypertensive Drugs: DocumentationBy the Time of Regulatory ApprovalBy the Time of Regulatory Approval

• Effect on major CVD mortality/morbidityEffect on major CVD mortality/morbidity• Optimal dose (risk-benefit balance)Optimal dose (risk-benefit balance)• Uncommon early side effects or clinical Uncommon early side effects or clinical

complicationscomplications• ADRs and complications of long-term drug useADRs and complications of long-term drug use• Efficacy or safety in various subgroupsEfficacy or safety in various subgroups• Effect on pregnancyEffect on pregnancy• Drug interactionsDrug interactions

UnknownUnknown

Aim of Antihypertensive Aim of Antihypertensive TherapyTherapy

To prevent the cardiovascular complications of To prevent the cardiovascular complications of hypertension -- stroke, acute myocardial infarction, hypertension -- stroke, acute myocardial infarction, congestive heart failure -- not just to lower an congestive heart failure -- not just to lower an elevated blood pressure.elevated blood pressure.

Eligibility criteria for meta-analysisEligibility criteria for meta-analysis

• Randomized placebo controlled trialsRandomized placebo controlled trials

• Treatment duration of Treatment duration of >> 1 year 1 year

• Assessment of major disease endpointsAssessment of major disease endpoints

• Unconfounded by other therapiesUnconfounded by other therapies

Psaty et al., JAMA 1997Psaty et al., JAMA 1997

Definition of Treatment StrategiesDefinition of Treatment Strategies

• Multiple agents used in most trialsMultiple agents used in most trials• Trials classified by first-line strategyTrials classified by first-line strategy

---- High-dose diuretic therapyHigh-dose diuretic therapy

---- Low-dose diuretic therapyLow-dose diuretic therapy

---- Beta-blocker therapyBeta-blocker therapy• No eligible trials evaluating CCBs or No eligible trials evaluating CCBs or

ACE inhibitorsACE inhibitors


Summary of Eligible Trials (n = 18)Summary of Eligible Trials (n = 18)

Low-dose diureticsLow-dose diuretics 4 4 4,3054,305 5,116 5,116

High-dose diureticsHigh-dose diuretics 1111 7,7687,768 12,07512,075

Beta-blockersBeta-blockers 4 4 6,7366,736 12,14712,147

HDFPHDFP 1 1 5,4845,484 5,455 5,455

TherapyTherapy TrialTrial InterventionIntervention ControlControl


Meta-analysis: AntihypertensivesMeta-analysis: Antihypertensives

EventEvent RRRR 95% CI95% CI

High-dose diureticsHigh-dose diuretics


Stroke 0.49 0.39-0.62

CHF 0.17 0.07-0.41

CHD 0.99 0.83-1.18

Total mortality 0.88 0.75-1.03



Low-dose diureticsLow-dose diuretics


Stroke 0.66 0.55-0.78

CHF 0.58 0.44-0.76

CHD 0.72 0.61-0.85




Beta-blockersBeta-blockers


Stroke 0.71 0.59-0.85

CHF 0.58 0.40-0.84

CHD 0.93 0.80-1.09


Summary of MajorSummary of Major FindingsFindings

• High-dose diuretic and ß-blocker therapies reduced High-dose diuretic and ß-blocker therapies reduced

the incidence of CHF and strokethe incidence of CHF and stroke

• Low-dose diuretic therapy reduced the incidence Low-dose diuretic therapy reduced the incidence

not only of CHF and stroke but also of CHD and not only of CHF and stroke but also of CHD and

total mortalitytotal mortality

• High-dose versus low-dose diuretic comparison High-dose versus low-dose diuretic comparison

was confounded by patient age was confounded by patient age


Syst-Eur -- Nitrendipine in ISHSyst-Eur -- Nitrendipine in ISH

• Randomized, placebo-controlled, 2N = 4,695Randomized, placebo-controlled, 2N = 4,695• Baseline, mean age 70 yrs, BP 174/85 mm HgBaseline, mean age 70 yrs, BP 174/85 mm Hg• Median FU of 2 yrs, BP Median FU of 2 yrs, BP 10/5 mm Hg10/5 mm Hg• Step-up drugs: enalapril (33%), HCTZ (20%)Step-up drugs: enalapril (33%), HCTZ (20%)• 237 randomized patients lost-to-follow-up237 randomized patients lost-to-follow-up• Reduction in stroke:Reduction in stroke: RR 0.58, 95% CI 0.40 - 0.83 RR 0.58, 95% CI 0.40 - 0.83 CHF: CHF: RR 0.71, 95% CI 0.47 - 1.10RR 0.71, 95% CI 0.47 - 1.10

Staessen et al., Lancet 1997Staessen et al., Lancet 1997

Concerns About Syst-EurConcerns About Syst-Eur

## randomized randomized 4,7364,736 vsvs 4,6954,695# primary events (stroke)# primary events (stroke) 262 262 vsvs 124 124# lost-to-follow-up# lost-to-follow-up 10 10 vsvs 237 237

Case-fatality, stroke (%)Case-fatality, stroke (%) 8.9 8.9 vsvs 27.3 27.3Case-fatality, CHF (%)Case-fatality, CHF (%) 6.4 6.4 vsvs 20.4 20.4

Questions in Syst-Eur:Questions in Syst-Eur: incomplete ascertainment?incomplete ascertainment?level of medical care?level of medical care?generalizable findings?generalizable findings?

SHEPSHEP Syst-EurSyst-Eur

Pahor et al., Lancet 1998Pahor et al., Lancet 1998

Captopril Prevention Project (CAPPP)Captopril Prevention Project (CAPPP)

DesignDesign Randomized, openRandomized, open

PopulationPopulation 10,985 hypertensives, aged 25-10,985 hypertensives, aged 25-66 years, with DBP 66 years, with DBP >> 100 mm Hg 100 mm Hg

InterventionIntervention Captopril (50-100 mg) Captopril (50-100 mg) vsvs clinician’s clinician’s choice of a diuretic or a ß-blocker; choice of a diuretic or a ß-blocker; diuretic or the other class as step-updiuretic or the other class as step-up

Follow-upFollow-up Average of 6.1 yearsAverage of 6.1 years

Hansson et al., Lancet 1999Hansson et al., Lancet 1999

Stroke, MI, CV deathStroke

0.33 0.5 1 2Relative Risk

MIDeath

CaptoprilCaptoprilbetterbetter

ConventionalConventionaltreatm. bettertreatm. better

Captopril Prevention Project - CAPPPCaptopril Prevention Project - CAPPP

Diabetes

OutcomeOutcome


Limitations of CAPPPLimitations of CAPPP

• Captopril only given once or twice per dayCaptopril only given once or twice per day

• Flawed randomization process (envelopes)Flawed randomization process (envelopes)

• Baseline difference on BP unlikely explained Baseline difference on BP unlikely explained by chanceby chance

• Potential differential evaluation of incident Potential differential evaluation of incident diabetes in the 2 groups due to lack of blindingdiabetes in the 2 groups due to lack of blinding

Cutler, Lancet 1999Cutler, Lancet 1999

Antihypertensive Treatment Antihypertensive Treatment in Type 2 Diabetesin Type 2 Diabetes

1.1. Active treatment Active treatment vsvs control (placebo) control (placebo)

2.2. More tight More tight vsvs less tight BP control less tight BP control

3.3. Comparisons of active treatmentsComparisons of active treatments

SHEP - CV Event Rate in ISHSHEP - CV Event Rate in ISH by Diabetes Statusby Diabetes Status

Curb et al., JAMA 1996Curb et al., JAMA 1996

Annualcardiovascular

event rate(%)

No diabetes Diabetes0

1

2

3

4

5

6

7

Active treatment

RR .66, 95%CI .55-.79

RR .66, 95%CI .46-.94Placebo

Syst-Eur -- Diabetic CohortSyst-Eur -- Diabetic CohortN

o. o

f N

o. o

f E

vent

sE

vent

s

Tuomilento et al., NEJM 1999Tuomilento et al., NEJM 1999

MortalityMortality Stroke Stroke Cardiac Events Cardiac Events

NitrendipineNitrendipinePlaceboPlacebo

0

5

10

15

20

25

302626

1616 1515

55

1515

NSNSp=0.02p=0.02

77

NSNS

UK Prospective Diabetes StudyUK Prospective Diabetes Study150/85 vs 180/105 mmHg BP Target

EndpointEndpoint RR RR 95% CI95% CI

Any endpoint 0.76 0.62-0.92Diabetes death 0.68 0.49-0.94Any death 0.82 0.63-1.08MI 0.79 0.59-1.07Stroke 0.56 0.35-0.89PAD 0.51 0.19-1.37Microvascular dis. 0.63 0.44-0.89n = 758 vs 390 UKPDS Group, BMJ 1998UKPDS Group, BMJ 1998

HOT - Rate of Major CV Events HOT - Rate of Major CV Events According to Randomized GroupsAccording to Randomized Groups

BP goalmmHg

p for trend0.005

p for trend 0.5


0

5

10

15

20

25

30

All n=18790 Diabetic n=1501

Rat

e/10

00 p

erso

n-y

ears

<90

<85

<80

FACET ABCD

UKPDS CAPPP

MIDAS

Comparative Trials in Hypertensives Comparative Trials in Hypertensives with Type 2 Diabetes or Impaired with Type 2 Diabetes or Impaired

Glucose MetabolismGlucose Metabolism

FACET - Fosinopril versus Amlodipine FACET - Fosinopril versus Amlodipine Cardiovascular Events TrialCardiovascular Events Trial

DesignDesign Prospective randomized trial

PatientsPatients Hypertension and type 2 diabetes

Sample sizeSample size 380 patients

Intervention Intervention Fosinopril / amlodipine open label

OutcomesOutcomes - Primary: serum lipids

- Secondary: CV events, BP

Follow-upFollow-up 2.5 to 3.5 years

Tatti et al., Diabetes Care 1998Tatti et al., Diabetes Care 1998


Cardiovascular Events in FACET

Stroke AMI

Rateper 100

person-years

0

12

3

4

5

101413

27

10

4

p=.03

40

The figures at top of the bars indicate the number of events

Any majorCV event

Hospit.Angina

Fosinopril n=189

Amlodipine n=191

ABCD TrialABCD Trial

DesignDesign Double-blind randomized trialEnalapril vs nisoldipineIntensive vs moderate BP control

PatientsPatients Type 2 diabetes, a normotensiveand a hypertensive group

OutcomesOutcomes - Primary: renal function - Secondary: CV events, BP

Follow-upFollow-up 5 years

Estacio et al., NEJM 1998Estacio et al., NEJM 1998

Nisoldipine Enalapril

10

12

14

Intensive Moderate

Nu

mb

er

of

Pa

tie

nts

4

1

1312

0

2

4

6

8

ABCD TrialABCD TrialRisk of Myocardial Infarction -Risk of Myocardial Infarction -

Intensive and Moderate GroupsIntensive and Moderate Groups


P= 0.03 P= 0.002P= 0.002

1015202530354045

Nu

mb

er

of

Pat

ien

ts

NisoldipineNisoldipine EnalaprilEnalapril

5 5

20

43

2522

05

Non-Fatal MI's All MI's All CV Events

ABCD TrialABCD TrialCardiovascular DiseaseCardiovascular Disease


P= 0.001 P= 0.001

P= 0.002

ABCD TrialABCD Trial

• The independent Data Safety Monitoring Committee recommended early termination of the hypertensive arm because of the 5-fold increase in risk of fatal and non-fatal AMI in the nisoldipine group compared to the enalapril group

• Those receiving the calcium antagonist were reassigned to the ACE inhibitor


UK Prospective Diabetes StudyUK Prospective Diabetes StudyDesignDesign Randomized trial comparing (a) Randomized trial comparing (a)

lessless tight tight vsvs tight BP control and (b) two tight BP control and (b) two forms of tight control forms of tight control

PatientsPatients Hypertensives with type 2 diabetesHypertensives with type 2 diabetes

InterventionIntervention Furosemide-based Furosemide-based vsvs captopril- or captopril- or atenolol-basedatenolol-based

OutcomesOutcomes Fatal and nonfatal CV eventsFatal and nonfatal CV events

Follow-upFollow-up 8.4 years8.4 years

UKPDS Group, BMJ 1998UKPDS Group, BMJ 1998

UK Prospective Diabetes StudyUK Prospective Diabetes Study

EndpointEndpoint RR RR 95% CI95% CIAny endpointAny endpoint 1.101.10 0.86-1.410.86-1.41Diabetes deathDiabetes death 1.271.27 0.82-1.970.82-1.97Any deathAny death 1.141.14 0.81-1.610.81-1.61MIMI 1.201.20 0.82-1.760.82-1.76StrokeStroke 1.121.12 0.59-2.120.59-2.12PADPAD 1.481.48 0.35-6.190.35-6.19Microvascular dis. Microvascular dis. 1.291.29 0.80-2.100.80-2.10

n = 400 vs 358 UKPDS Group, BMJ 1998UKPDS Group, BMJ 1998

Captopril vs Atenolol (reference group)Captopril vs Atenolol (reference group)

Stroke, MI, CV death

Stroke

0.33 0.5 1 2Relative Risk

MIDeath

Captoprilbetter

Conventionaltreatm. better

CAPPP - patients with diabetesCAPPP - patients with diabetesOutcome


MIDAS TrialMIDAS Trial• 883 hypertensive patients randomized to 883 hypertensive patients randomized to

isradipine or HCTZ and followed for 3 yearsisradipine or HCTZ and followed for 3 years

• No difference in carotid intimal medial thickness, No difference in carotid intimal medial thickness, the primary outcomethe primary outcome

• Increased risk of major CV events by 78% Increased risk of major CV events by 78% (p=0.07) and all CV events and procedures by (p=0.07) and all CV events and procedures by 63% (p=0.02) in the isradipine group63% (p=0.02) in the isradipine group

Borhani et al., JAMA 1996Borhani et al., JAMA 1996

MIDAS Trial - Relative Risk of CV MIDAS Trial - Relative Risk of CV Events for Isradipine versus HCTZEvents for Isradipine versus HCTZ

*p<.05

Byington et al., Diabetes Care 1998Byington et al., Diabetes Care 1998

HbA1c %

RR

Serum insulin U/ml

1.81

1.16

2.71*

1.25

3.22*

0

1

2

3

4

All <6.7 6.7+ <9.8 9.8+

Blood Pressure Changes in FACET

mmHg

*p .05 amlodipine vs fosinopril.

Baseline 1 2 3

Follow-up time (years)

Fosinopril Amlodipine

60

80

100

120

140

160

180 Systolic

Diastolic

*


The Appropriate Blood Pressure The Appropriate Blood Pressure Control in Diabetes (ABCD) TrialControl in Diabetes (ABCD) Trial

Adapted from Estacio RO et al., NEJM 1998Adapted from Estacio RO et al., NEJM 1998

Intensive-Treatment Group

70

90

110

130

150

0 6 12 18 24 30 36 42 48 54 60

Month

No. of patients 237 189 199 176 166 137

Nisoldipine

EnalaprilSystolic

DiastolicBlo

od

Pre

ssu

re

(m

m H

g)

Systolic Blood Pressure Reduction Systolic Blood Pressure Reduction and Cardiovascular Events in FACET and Cardiovascular Events in FACET

Amlodipine

p<.05p<.01

Fosinopril

Pahor et al., J Cardiovasc Pharmacol 1998Pahor et al., J Cardiovasc Pharmacol 1998

-20-23

-20

-32-35

-30

-25

-20

-15

-10

-5

0

mm

Hg No events

Events

One-year Diastolic BP Reduction and Cardiovascular Events in MIDAS

Isradipine

p=.03

HCTZ

p=.01

Byington et al., Byington et al., Diabetes CareDiabetes Care 1998 1998

-20

-15

-10

-5

0

mm

Hg No events

Events

Comparative Trials of Comparative Trials of Antihypertensive Agents in DiabetesAntihypertensive Agents in Diabetes

• Blood pressure alone is not a sufficient marker of drug Blood pressure alone is not a sufficient marker of drug efficacyefficacy

• Pronounced reductions may be harmful in diabeticsPronounced reductions may be harmful in diabetics• Health benefits may differ among antihypertensive agentsHealth benefits may differ among antihypertensive agents• ACE inhibitors appear to be most beneficial; calcium ACE inhibitors appear to be most beneficial; calcium

antagonists least beneficialantagonists least beneficial

Demonstrate that:Demonstrate that:

Other Benefits of ACE Other Benefits of ACE Inhibitors in DiabetesInhibitors in Diabetes

0

10

20

30

40

50

60

70

BaselineBaseline 6 months6 months 12 months12 months

Lisinopril (10-20mg o.d)Lisinopril (10-20mg o.d)

Nifedipine (20-40 mg b.d)Nifedipine (20-40 mg b.d)

BRILLIANTBRILLIANTUrinary Albumin ExcretionUrinary Albumin Excretion

Uri

na

ry a

lbu

min

exc

reti

on

Uri

na

ry a

lbu

min

exc

reti

on

(mic

rog

/min

)(m

icro

g/m

in)

**

*p=0.0006*p=0.0006

Agardh et al., J Human Hypertens 1996Agardh et al., J Human Hypertens 1996

ACE Inhibitors and Microvascular ACE Inhibitors and Microvascular Disease in Diabetic PatientsDisease in Diabetic Patients

• ACEIs delay the development and progression of diabetic ACEIs delay the development and progression of diabetic nephropathy*nephropathy*

• ACEIs markedly slow progression of retinopathy**ACEIs markedly slow progression of retinopathy**

• ACEIs appear to improve peripheral neuropathy*** ACEIs appear to improve peripheral neuropathy***

* Ahmad et al., Diabetes Care 1997* Ahmad et al., Diabetes Care 1997 * Maschio et al., NEJM 1996* Maschio et al., NEJM 1996 ** Chaturvedi et al., Lancet 1998** Chaturvedi et al., Lancet 1998*** Malik et al., Lancet 1998*** Malik et al., Lancet 1998

Short-term mortality benefit of ACE Short-term mortality benefit of ACE Inhibitors in Diabetic Patients with Inhibitors in Diabetic Patients with

Acute MIAcute MI%%

of ptsof pts

LisinoprilLisinopril ControlControl

NIDDNIDD IDDIDDZuanetti & Latini, J Diabetes Complications 1997Zuanetti & Latini, J Diabetes Complications 1997

0

5

10

15

20

25

810.6 11.8

21.1

LisinoprilLisinopril ControlControl

p <0.05p <0.05

p <0.05p <0.05

Safety DocumentationSafety Documentation

• More than 100,000 person-years desiredMore than 100,000 person-years desired

• Safety problems common across indicationsSafety problems common across indications

• Extensive safety documentation for diuretics, Extensive safety documentation for diuretics, beta-blockers and ACE inhibitorsbeta-blockers and ACE inhibitors

• Inadequate documentation of long-term safety Inadequate documentation of long-term safety for calcium antagonists, alpha-blockers, for calcium antagonists, alpha-blockers, angiotension II blockersangiotension II blockers

Safety Documentation for Slow-ReleaseSafety Documentation for Slow-ReleaseCAs in HypertensionCAs in Hypertension

Adalat CCAdalat CC 31 31 10 10Procardia XLProcardia XL 56 56 36 36PlendilPlendil 39 39 14 14NorvascNorvasc 269 269 158 158CardeneCardene 53 53 22 22Cardizem SRCardizem SR 138 138 115 115Dilacor XRDilacor XR 24 24 7 7IsoptinIsoptin 1 1 1 1VerelanVerelan 5 5 2 2

TotalTotal 616 (x = 68)616 (x = 68) 365 (x = 41)365 (x = 41)

DrugsDrugs ActiveActive ControlControlPerson-yearsPerson-years

Risk of Primary Cardiac ArrestRisk of Primary Cardiac Arrest

ß-blockerß-blocker 1.01.0 referencereferenceThiazide, 100 mgThiazide, 100 mg NoNo 2.42.4 0.7-8.80.7-8.8Thiazide, 50 mgThiazide, 50 mg NoNo 1.11.1 0.5-2.50.5-2.5Thiazide, 25 mgThiazide, 25 mg NoNo 0.70.7 0.2-2.50.2-2.5Thiazide, 50 mgThiazide, 50 mg YesYes 0.50.5 0.1-2.20.1-2.2Thiazide, 25 mgThiazide, 25 mg YesYes 0.30.3 0.1-1.00.1-1.0

TherapyTherapy K-sparing RR K-sparing RR 95% CI 95% CI

Siscovick et al., N Engl J Med 1994Siscovick et al., N Engl J Med 1994

CCBs in HypertensionCCBs in HypertensionPotential Serious Adverse EventsPotential Serious Adverse Events

• Coronary eventsCoronary events• Bleeding (GI and surgical)Bleeding (GI and surgical)• Cancer (blocking apoptosis)Cancer (blocking apoptosis)• Cerebral white matter lesions (MRI)Cerebral white matter lesions (MRI)• OthersOthers

• Strong association to drug dose and duration of Strong association to drug dose and duration of exposure support causationexposure support causation

CAs safety - Non Randomized CAs safety - Non Randomized Studies and Meta-analysisStudies and Meta-analysis

CAs10

54

6

2

5

10 0

0

2

4

6

8

10

12

CVD, death Bleeding Cancer

Nu

mb

er

of r

ep

ort

s

increase risk

neutral

reduce risk

Pahor et al., (to be published)Pahor et al., (to be published)

Hypertensive EmergenciesHypertensive Emergencies• IR nifedipine widely used in hypertensive emergencies and IR nifedipine widely used in hypertensive emergencies and

even moderately elevated BP in asymptomatic patientseven moderately elevated BP in asymptomatic patients• Never approved by the FDA for this indication; complete Never approved by the FDA for this indication; complete

lack of outcome datalack of outcome data• Unpredictable BP fall associated with stroke, acute MI, Unpredictable BP fall associated with stroke, acute MI,

severe hypotension and deathsevere hypotension and death• ““Routine use of IR nifedipine in hypertensive emergencies Routine use of IR nifedipine in hypertensive emergencies

and pseudoemergencies should be abandoned”and pseudoemergencies should be abandoned”

Grossman et al., JAMA 1996Grossman et al., JAMA 1996

Hypertension Optimal Hypertension Optimal Treatment Trial (HOT)Treatment Trial (HOT)

18,790 hypertensives randomized to three DBP goals: < 90, < 85 and < 80 mm Hg.

Achieved mean DBP: 85.2, 83.2 and 81.1 mm Hg. No difference in incidence of major CV events:

9.9, 10.0 and 9.3/1,000 pt. years. Post-hoc analysis suggested benefit of lower DBP

among diabetics. Offset by increase in events among non-diabetics. .


Interpretation of HOT ResultsInterpretation of HOT ResultsMRFITMRFIT 5.8 mm Hg lower DBP associated with lower stroke 5.8 mm Hg lower DBP associated with lower stroke

(44%) and CHD (25%) risks(44%) and CHD (25%) risks

HDFPHDFP Mean 5.4 mm Hg reduction in DBP translated into Mean 5.4 mm Hg reduction in DBP translated into 17% mortality and 35% stroke benefit17% mortality and 35% stroke benefit

HOTHOT Mean 4.0 mm Hg reduction in DBP between Mean 4.0 mm Hg reduction in DBP between << 90 90 and and << 80 target groups translated into a 7% lower 80 target groups translated into a 7% lower CV event rate (N.S.)CV event rate (N.S.)

ExplanationsExplanations (1) Null hypothesis true (unlikely)(1) Null hypothesis true (unlikely)

(2) Higher doses of felodipine (2) Higher doses of felodipine increased CV event increased CV event

offsetting offsetting benefit of BP lowering itself benefit of BP lowering itself (likely(likely) )

(3) Insufficient power(3) Insufficient power

Antihypertensive and Lipid Antihypertensive and Lipid Lowering Treatment to Prevent Lowering Treatment to Prevent

Heart Attack Trial (ALLHAT)Heart Attack Trial (ALLHAT)DesignDesign Randomized, double-blind clinical Randomized, double-blind clinical

trialtrial

PatientsPatients 42,451 hypertensives; 15,290 diabetics42,451 hypertensives; 15,290 diabetics

InterventionIntervention Lisinopril, amlodipine and doxazosinLisinopril, amlodipine and doxazosincompared to chlorthalidone compared to chlorthalidone Same BP goal -- 140/90 mm HgSame BP goal -- 140/90 mm Hg

EndpointsEndpoints Fatal and nonfatal CV eventsFatal and nonfatal CV events

Follow-upFollow-up Approximately 6 yearsApproximately 6 years

ConclusionsConclusions• ACEIs appear to convey similar antihypertensive benefits as ACEIs appear to convey similar antihypertensive benefits as

the established first-line agents low-dose diuretics and beta-the established first-line agents low-dose diuretics and beta-blockersblockers

• ACEIs are the antihypertensive drugs of choice in ACEIs are the antihypertensive drugs of choice in hypertensives with type 2 diabeteshypertensives with type 2 diabetes

• ACEIs are recommended in diabetic patients with nephropathy ACEIs are recommended in diabetic patients with nephropathy and myocardial infarctionand myocardial infarction

• CCBs should be 4th-line agents in diabeticsCCBs should be 4th-line agents in diabetics

Ordering of Slide SetOrdering of Slide Set

If you wish to order an electronic copyIf you wish to order an electronic copyof this slide set, “Recent Developments inof this slide set, “Recent Developments inthe Treatment of Hypertension,” pleasethe Treatment of Hypertension,” pleasecontact Ms. Sarah Hutchens, Wake Forestcontact Ms. Sarah Hutchens, Wake ForestUniversity School of Medicine at:University School of Medicine at:

[email protected]@rc.phs.wfubmc.edu

The slide set is in PowerPoint Version 4.0.The slide set is in PowerPoint Version 4.0.

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Recent Developments in the Treatment of Hypertension Recent Developments in the Treatment of...

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